BRAF

V-RAF murine sarcoma viral oncogene homolog B1 (BRAF)

BRAF Biology

The RAS-RAF-MEK-ERK pathway is an important protein kinase cascade that regulates cell differentiation, proliferation, and survival in response to hormones, cytokines, and growth factors.1,2 There are 3 functional RAF proteins in humans, including V-Raf murine sarcoma viral oncogene homolog B (BRAF).2 BRAF is a serine/threonine-specific protein kinase with 3 conserved domains: CR1, CR2, and CR3.3 The wild-type BRAF protein forms a strong hydrophobic interaction in residues 596-600, which keeps it in its inactive state. BRAF becomes activated once the activation loop is phosphorylated, destabilizing the hydrophobic site and enabling downstream kinase activity.2

BRAF mutation is an acquired gene mutation more common in older patients (>60 years), proximal tumor location, locally advanced characteristics, and poor cell differentiation.1 The BRAF V600E mutation is associated with worse survival after recurrence in patients with stage III colon cancer and is associated with a shorter median progression-free and median overall survival than patients with wild-type BRAF tumors.4,5

Mutations in BRAF can result in constitutive activation of the BRAF gene, which stimulates tumor growth.6 BRAF mutations are more common in cancer types that also harbor RAS mutations, including colorectal cancer, borderline ovarian cancers, and malignant melanoma.7 This association occurs because activation of the RAS-RAF-MEK-ERK pathway can be achieved by cancer cells through mutation at various points along the pathway.5,7 Therefore, agents that target BRAF gain synergistic effects when combined with other agents that target kinases in the same pathway.

BRAF V600E Testing

Patients with metastatic colorectal cancer (mCRC) should have their tumor genotyped with a next-generation sequencing (NGS) panel in a CLIA-certified laboratory that is qualified to perform high-complexity molecular pathology testing. BRAF V600E may also be tested with immunohistochemistry (IHC).8 Testing may be performed on either the primary tumor or the metastases.8

BRAF V600E Targeted Therapy

A single drug regimen is FDA-approved for treating adult patients with mCRC with a BRAF V600E mutation detected by an FDA-approved test after prior therapy: encorafenib in combination with cetuximab.6,8–10 NCCN guidelines version 1.2024 also recommend encorafenib in combination with panitumumab.8 Encorafenib is a kinase inhibitor of BRAF V600E, wild-type BRAF, and CRAF.6 Cetuximab is an epidermal growth factor receptor (EGFR) inhibitor.11

Learn more about Encorafenib >

References

  1. Clancy C, Burke JP, Kalady MF, Coffey JC. BRAF mutation is associated with distinct clinicopathological characteristics in colorectal cancer: a systematic review and meta-analysis. Colorectal Dis. 2013;15(12):e711-e718. doi:10.1111/codi.12427
  2. Wan PTC, Garnett MJ, Roe SM, et al. Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF. Cell. 2004;116(6):855-867. doi:10.1016/s0092-8674(04)00215-6
  3. Cutler RE, Stephens RM, Saracino MR, Morrison DK. Autoregulation of the Raf-1 serine/threonine kinase. Proc Natl Acad Sci USA. 1998;95(16):9214-9219. doi:10.1073/pnas.95.16.9214
  4. Sinicrope FA, Shi Q, Allegra CJ, et al. Association of DNA mismatch repair and mutations in BRAF and KRAS with survival after recurrence in stage III colon cancers. JAMA Oncol. 2017;3(4):472-480. doi:10.1001/jamaoncol.2016.5469
  5. Tol J, Nagtegaal ID, Punt CJ. BRAF mutation in metastatic colorectal cancer. N Engl J Med. 2009;361(1):98-99. doi:10.1056/nejmc0904160
  6. Braftovi (Encorafenib). Package insert. Array BioPharma, Inc; 2023.
  7. Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature. 2002;417(6892):949-954. doi:10.1038/nature00766
  8. NCCN. Clinical Practice Guidelines in Oncology. Colon cancer, version 1.2024. https://www.nccn.org/professionals/physician_gls/pdf/colon.pdf
  9. Tabernero J, Grothey A, Van Cutsem E, et al. Encorafenib plus cetuximab as a new standard of care for previously treated BRAF V600E-mutant metastatic colorectal cancer: Updated survival results and subgroup analyses from the BEACON study. J Clin Oncol. 2021;39(4):273-284. doi:10.1200/JCO.20.02088
  10. FDA approves encorafenib in combination with cetuximab for metastatic colorectal cancer with a BRAF V600E mutation. US FDA. Updated April 9, 2020. Accessed May 21, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-encorafenib-combination-cetuximab-metastatic-colorectal-cancer-braf-v600e-mutation.
  11. Erbitux (cetuximab). Package insert. Eli Lilly and Company; 2021. https://uspl.lilly.com/erbitux/erbitux.html#pi